Glycogen synthase kinase (GSK) -3? and -3? are unique protein kinases in that they are active in cells under unstimulated conditions but are inhibited by phosphorylation of specific N-terminal serine residues. Constitutive activation of GSK-3? attenuates cardiac hypertrophy and dysfunction in response to pressure overload, whereas constitutive activation of GSK-3? exacerbates them, suggesting that GSK-3? and GSK-3? have distinct functions in the heart. Despite their structural similarity, GSK-3? and GSK-3? have distinct, subcellularly compartmentalized, and often opposite, functions. Our long term goal is to elucidate the isoform-specific functions of GSK-3?/? in the heart. Here we will focus on the novel function of GSK-3? in mediating cardiac dysfunction in response to obesity and insulin resistance. GSK-3? is activated in the hearts of obese mice fed a high-fat diet (HFD). Activation of GSK-3? in the nucleus phosphorylates PPAR? at S280 in the ligand-binding domain (LBD) and stimulates the transcriptional activity of PPAR?. Together with the fact that haploinsufficiency of GSK-3? protects the heart from cardiac hypertrophy and diastolic dysfunction in response to HFD, these findings suggest that GSK-3? is involved in the pathogenesis and development of cardiac dysfunction in response to obesity and insulin resistance through S280 phosphorylation of PPAR?. Our overall hypothesis is that GSK-3? excessively activates PPAR? transcriptional activity through phosphorylation of PPAR? at S280 and enhanced heterodimerization with RXR?, thereby causing metabolic derangement in the heart subjected to obesity or insulin resistance. Synthetic ligands for PPAR? prevent S280 phosphorylation by interfering with GSK-3?-PAR? interaction at the LBD, thereby alleviating metabolic derangement in response to HFD. To test this hypothesis, we will use cardiac-specific GSK-3? knock-out mice and mice expressing PPAR? 280 phosphorylation-resistant and -mimicking mutants in combination with proteomic approaches and metabolic analyses. The knowledge obtained from this study should be useful for developing new specific strategies to limit myocardial damage in patients with obesity or insulin resistance through specific modulation of GSK-3? and /or S280 phosphorylation of PPAR?.